How cell growth and proliferation are coordinated with metabolism and the metabolic state of a cell remains poorly understood. Previous studies have established that cells must attain a sufficiently favorable metabolic state in order to initiate a program of growth and division. Knowledge of these mechanisms that connect cellular metabolism to cell growth control will provide novel strategies for the treatment of complex metabolic diseases such as cancer. This research proposal aims to understand the mechanisms by which key metabolic and nutritional signals ultimately control cell growth and proliferation. A unique model system wherein a highly synchronized yeast cell population undergoes robust oscillations in oxygen consumption during continuous growth will be used to investigate such mechanisms of growth control. During these metabolic cycles, cell division is precisely gated to a temporal window when the rate of cellular oxygen consumption decreases substantially, which is highly reminiscent of cancer cell division. Cell division initiates only following completion of a burst of mitochondrial respiration that is accompanied by a transient upregulation of growth genes. Just prior to entry into this growth phase, the cell population exists in a metabolic phase that resembles quiescence or G0. Interestingly, addition of select metabolites can trigger exit from this quiescent phase and induce immediate entry into the growth phase. These metabolites are key activators of growth control pathways. This yeast metabolic cycle system will be utilized to understand how cell growth and proliferation are precisely coordinated with metabolic signals and cellular metabolic state. This outstanding problem will be addressed by investigating the mechanisms by which carbon sources signal commitment to growth. In parallel, this system will be used to understand how the conserved TOR growth control pathway becomes active during the switch to growth. PUBLIC HEALTH RELEVANCE: We have established a model system that will enable the study of the metabolic and nutritional signals that ultimately control cell growth and proliferation. We hope these studies will provide novel insights into the mechanisms of cell growth control and contribute towards our understanding of complex metabolic diseases such as cancer.